Inhibition of Thr-55 phosphorylation restores p53 nuclear localization and sensitizes cancer cells to DNA damage.
The p53 tumor suppressor induces cell growth arrest and apoptosis in response to DNA damage. Because these functions are achieved largely by the transcriptional properties of p53, nuclear localization of the protein is essential. Indeed, the tumors with aberrant cytoplasmic localization of wild-type p53 often exhibit an impaired response to DNA damage. In this study, we report that Thr-55 phosphorylation induces the association of p53 with the nuclear export factor CRM1, leading to p53 nuclear export. We further show that MDM2 also promotes the CRM1-p53 association and Thr-55 phosphorylation is required for this process. Interestingly, inhibition of Thr-55 phosphorylation by a dietary flavonoid, apigenin, specifically blocks the CRM1-p53 association, restores p53 nuclear localization, and sensitizes tumor cells with cytoplasm localized wild-type p53 to DNA damage. These data provide insights into the regulation of p53 nuclear localization by post-translational modification and suggest an avenue for targeted therapy for cancers caused by aberrant cytoplasm localization of wild-type p53.
Cai
Xin
X
Department of Biochemistry, University of California, Riverside, CA 92521, USA.
Liu
Xuan
X
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D047310:Apigenin / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D008954:Models, Biological; D009447:Neuroblastoma / Q000378:metabolism; D010766:Phosphorylation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013912:Threonine / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis* / Q000378:metabolism*; D000097606:Exportin 1 Protein
D000970:Antineoplastic Agents; D047310:Apigenin; D005047:Etoposide; D028884:Karyopherins; D051736:Proto-Oncogene Proteins c-mdm2; D018160:Receptors, Cytoplasmic and Nuclear; D013912:Threonine; D016159:Tumor Suppressor Protein p53; D000097606:Exportin 1 Protein